BAG3, a 74 kDa cytoplasmic protein, belongs to the family of co-chaperonins that interact with the ATPase domain of the protein HSP70 (Heat Shock Protein 70) through the structural domain known as the BAG domain. Furthermore, BAG3 protein contains a WW domain (Trp-Trp), a proline-rich region (PXXP), and two conserved motifs IPV (Ile-Pro-Val), which can mediate binding to other proteins. Thanks to the nature of BAG3 protein as an adapter (attributable to the presence of many functional domains), such protein can therefore interact with different proteins. In humans, bag3 gene expression is constitutive in few kinds of normal cells, including myocytes, while mutations thereof are associated with diseases of the skeletal and cardiac muscles. Moreover, BAG3 protein is expressed in many types of primary tumours or tumour cell lines (lymphoid or myeloid leukemias, neuroblastoma, pancreatic cancer, thyroid cancer, breast and prostate cancer, melanoma, osteosarcoma, and glioblastoma, and tumours of the kidney, colon, and ovary). In normal cell types, such as leukocytes, epithelial and glial cells and cells of the retina, bag3 gene expression can be induced by stressing agents, such as oxidants, high temperatures, lack of serum, heavy metals, HIV-1 infections, etc. These data indicate that bag3 gene expression regulation is an important component in the cellular response to stress and is correlated with the presence of elements that respond to HSF1 (Heat Shock Transcription Factor 1), which is activated in various forms of cell stress in the BAG3 gene promoter (Franceschelli S., et al. J Cell Physiol 215 (2008) 575-577).
Moreover, due to the presence of many protein-protein interaction domains in the structure thereof, BAG3 protein influences cell survival in different types of cells, interacting with different molecular partners. (A. Rosati et al. Biochim Biophys Acta. 2012; 1826:365-9).
The first mechanism reported in relation to BAG3 anti-apoptotic activity was identified in osteosarcoma and melanoma cells, where it was observed that BAG3 protein modulates the activation of transcription factor NF-kB and cell survival (Ammirante M. et al., Proc Natl Acad Sci USA 107 (2010) 7497-7502). A different molecular mechanism has been described in glioblastoma cells, where BAG3 protein cooperates in a positive way with HSP70 protein to maintain BAX protein in the cytosol and prevent the translocation thereof into the mitochondria (Festa M. et al., Am J Pathol 178 (2011) 2504-25). Finally, in some tumours, BAG3 has been shown to regulate proteins that modulate cell adhesion.
The presence of cytoplasmic BAG3 protein has also been described in many different cellular systems and has been associated, not only with various tumours, but also in diseases in general related to cell survival.
It has recently been demonstrated that BAG3 protein can be secreted by certain cells, in particular by pancreatic adenocarcinoma cells and by cardiomyocytes when subjected to an oxidative stress. (Rosati et al., Am J Pathol. 2012 November; 181(5):1524-9; De Marco et al. Cell Death Dis. 2013; 4:e495.). Patent application n. WO2011/067377 describes soluble BAG3 protein, i.e. the said protein when it is secreted by the cells, as a biochemical marker in serum which is highly specific for the diagnosis of certain pathological conditions, such as cardiac diseases and tumour of the pancreas. In particular, it has been demonstrated that, in patients suffering from pancreatic adenocarcinoma, the soluble BAG3 concentration is generally higher than 10 ng/ml, significantly higher than in the serum of healthy individuals. Furthermore, it has recently been reported that BAG3 protein is expressed in 346/346 patients with pancreatic ductal adenocarcinoma (PDAC) and is released by the cells of the tumour of the pancreas, but such protein is not expressed in either the surrounding non-neoplastic tissues or in a normal pancreas; likewise, it has been reported that the levels of expression of BAG3 are related to patient survival. In particular, it has been demonstrated that the BAG3 protein secreted by tumour cells in the pancreas induces the activation of macrophages and the production, thereby, of molecules that support neoplastic growth and, in the heart, are responsible, after an ischemic event, for the phagocytosis of the damaged myocytes and for the replacement of the necrotic myocardium with scar tissue and the consequent tissue remodelling.
Patent application n. MI2013A000403 also describes how the inhibition of the BAG3 protein through the use of monoclonal anti-BAG3 antibodies impairs development of pancreatic tumours. Indeed, by interfering with the binding of BAG3 to macrophages, through a monoclonal anti-BAG3 antibody, the activation of macrophages and tumour growth is inhibited. Treatment with anti-BAG3 antibodies represents a new, more effective therapeutic tool for the management of tumours of the pancreas.
As is known, conventional chemotherapy treatments for tumour diseases, as well as treatments of inflammatory and immune diseases with corticosteroids or NSAIDs (non-steroidal anti-inflammatory drugs) pose numerous drawbacks linked to side effects and are not, at present, definitive means of managing such diseases.
There is, therefore, an evident need for a new and improved therapeutic treatment which has the advantage of being highly specific and having few or indeed no side effects, as compared with the conventional, commonly known therapies used for the management of the diseases of an immune, inflammatory, cardiac and neoplastic nature described in the present invention.